ITMI20000261A1 - PROCESS FOR THE PREPARATION OF PYRIDYLIDEN-PHTHALIDES - Google Patents

Description

Process for the preparation of (pyridinylidene) -phthalides

Description

The present invention relates to a process for the preparation of (pyridinylidene) -phthalides and, more particularly, it relates to a process for the preparation of (pyridinylidene) -phthalides starting from 3-oxo-1,3-dihydroisobenzofuran-1-carboxylic acids and pyridincarbaldehydes.

The (pyridinylidene) - phthalides are known compounds, described in the literature.

In international patent applications WO 98/35958 in the name of Novartis and WO 00/05218 in the name of the same applicant, different (pyridinylidene) - phthalides are used as intermediates useful for the preparation of phthalazines endowed, respectively, with inhibitory activity on angiogenesis and on PDE4 enzyme.

Numerous methods are known for the synthesis of arylidene phthalides and some of these, in particular, have been used to prepare (pyridinylidene) -phthalides.

For example J. Ploquin et al, in J. Het. Chem. (1980), 17, 961 report the preparation of (pyridinylidene) -phthalides by heat condensation between phthalic anhydride and methyl-pyridine. However, this reaction is of little application interest since, in addition to presenting poor yields, it is limited to obtaining unsubstituted or symmetrically substituted derivatives on the phthalic ring. In fact, an asymmetric substitution would inevitably lead to the formation of regioisomers that are difficult to separate.

A different process to prepare, inter alia, (pyridinylidene) -phthalides also asymmetrically substituted, reported in the aforementioned patent application WO 00/05218, is based on the Wittig condensation between a salt of phosphonium XI and an aldehyde XII as shown here schematized :

in which A also represents pyridine and Z 'may be absent.

However, the process in question, despite having a practically quantitative yield, has a series of drawbacks which make it of little industrial interest. In fact the preparation of the salt of phosphonium XI, which takes place according to the following scheme

shows some critical points. In particular, the radical bromination reaction of IX is strongly exothermic, the resulting brominated product X is unstable and therefore must be used as soon as possible in the reaction with triphenylphosphy to give the phosphonium salt XI. Finally, during this last step there is a significant increase in the molecular weight of the substrate which leads to an undesirable increase in the reaction mass. Furthermore, in the subsequent Wittig reaction, the formation of equimolar quantities of phosphine oxide occurs, which further complicates the synthetic feasibility.

All these problems make the aforementioned process difficult on an industrial level.

Among the alternative methods known to prepare arylidene phthalides, the one described by R. H. Prager et al, in Tetrahedron, (1984), 40, 1517 which uses variously substituted benzaldehydes (4) and 3-oxo-1,3-dihydro- acid is of particular interest. 1-isobenzofuranecarboxylic (1) as starting products.

In all the cases examined, the reaction, carried out by directly heating the mixture of reagents, leads to the formation of mixtures of 3 -aryliden- phialides (3) and 3- (arylhydroxymethyl) -phthalides (2) in variable ratios, with overall yields from 47 at 90%:

The authors study the course of the decarboxylation-condensation reaction reported above by varying some experimental parameters, such as the type and amount of aldehyde, the absence or presence of solvent, the reaction time and temperature. As regards the influence exerted by the aldehyde substituents (4) on the reaction course, the authors declare that "only in the case of electron donor groups, only the dehydration product (3) is obtained" (see lines 2-4, 1 < a> column, page 1519).

Furthermore, the reaction seems to be advantageous only if carried out in the absence of solvent while it is clearly disadvantaged if carried out in its presence. In particular in apolar solvents at 140 ° C it does not happen, while in the case of polar solvents, such as eg. dimethyl sulfoxide, leads exclusively to obtaining alcohol (2) with poor yields and only with significant excesses (2-6 equivalents) of aldehyde (see from line 19 onwards, 1 column, page 1519). Furthermore, the dehydration of (2) to (3) does not occur appreciably in this solvent.

Therefore, from the work presented by Rolf H. Prager et al, it can be concluded that in order to directly obtain the compounds of formula (3) with significant yields, the aforementioned reaction should be carried out starting from electron-rich aldehydes (4) by energetic heating in the absence of solvent .

Instead we have surprisingly found that even using electron-poor aldehydes such as pyridincarbaldehydes, even in an almost stoichiometric ratio, it is possible to directly obtain the corresponding arylidene phthalides with high yields if the reaction is carried out in the presence of anhydrides.

In this regard, it has been hypothesized that the anhydride, in addition to carrying out the probable function of dehydrator, is directly involved in the initial activation of the carboxylic function of the 3-oxo-1,3-dihydro-isobenzofuran-1-carboxylic acids. Therefore, the object of the present invention is a process for the preparation of pyridinylidene-phthalides having formula

Py represents a 2, 3 or 4-pyridinyl group optionally substituted by one or more substituents selected from halogen, nitro, cyano, bone and carboxy groups;

R and R1, the same or different from each other, represent hydrogen, C1-C6 alkyl or an OR2 group in which R2 represents a linear or branched C1-C6 alkyl, a C4-C7 cycloalkyl or a C1-C6 polyfluoroalkyl;

the bond indicates both isomers E and Z;

by reaction of a compound of formula

in which R and R1 have the meanings reported above;

with an aldehyde of the formula

where Py has the above meaning;

by heating the mixture of compounds of formula II and III in the presence of an anhydride and possibly in a mixture with a suitable solvent.

The process object of the present invention is easy to carry out and allows to obtain pyridinylidene-phthalides of formula I with good yields without using the aforementioned phosphonium XI salt.

The process object of the present invention provides for the reaction between a compound of formula II and a compound of formula III.

The compounds of formula II are known and can be easily prepared for example according to the synthesis route described in J. Chem. Soc. (1929), 200.

In the compounds of formula II the groups R and R1 have the meanings reported above. Particularly preferred compounds of formula II are those in which at least one of R and R1 represents OR2, even more preferred are those in which one or both of R and R1 are OCH3.

The starting compounds of formula III are also generally known, commercially available or can be prepared according to processes reported in the literature. Particularly preferred compounds of formula III are those in which Py represents a 4-pyridinyl group, even more preferred if Py represents a dialosubstituted 4-pyridinyl residue.

In the process object of the present invention the compounds of formula III are generally used with respect to the compounds of formula II in a molar ratio of between 0.5 and 4. Preferably they are used in a ratio of between 0.8 and 1.5, even more so. preferably between 0.9 and 1.1.

This process is conducted in the presence of an anhydride.

The term "anhydride" refers to a reagent selected from the group of organic or inorganic anhydrides, respectively derived from organic or inorganic acids, or mixed, including in this class also the acyl, alkyl and arylsulfonyl halides.

Examples of anhydrides that can be used in the present process are, in the case of organic anhydrides, acetic, trifluoroacetic or trifluoromethanesulfonic anhydride, in the case of inorganic anhydrides, phosphoric, sulfuric anhydride or thionyl chloride, while among the mixed anhydrides, acetyl, tosyl or mesyl chloride.

Organic anhydrides are particularly preferred.

For practical reasons it is preferred to use acetic anhydride.

In the process object of the present invention the anhydride mentioned above can be used in considerable excess with respect to the starting compound of formula II also performing the function of solvent, for example in a molar ratio of 10: 1 with respect to the compound of formula II.

Alternatively, the anhydride can be used with respect to compound III in a more limited molar ratio, for example between 1 and 3. In this case, the reaction may require the presence of a suitable co-solvent.

In this regard, examples of usable solvents are high-boiling non-polar solvents, such as, for example, aromatic hydrocarbons, possibly chlorosubstituted.

Preferred aromatic solvents are toluene, xylene and chlorobenzene, particularly preferred is toluene.

For practical reasons it is preferred to carry out the process object of the present invention in excess of acetic anhydride.

The use of other activating systems, such as Lewis acids, or dehydrating agents, such as the distillation of suitable azeotropic mixtures, as an alternative to anhydride, also falls within the spirit of the present invention.

This process is carried out by heating the mixture of compounds of formula II and III, in the presence of anhydride and possibly the appropriate solvent.

Preferably the reaction mixture is heated to the reflux temperature. The process object of the present invention allows to obtain a final raw product, essentially consisting of the E / Z mixture of the compounds of formula I, which can be used directly without further purification treatments.

The compounds of formula I, prepared according to the process object of the present invention, can for example be used directly in the synthesis of PDE4 inhibitors with a phthalazine structure, as described in the aforementioned international application WO 00/05218.

The present process is preferably applied to the synthesis of 4-pyridinyl derivatives, even more preferably to the synthesis of dialo-substituted 4-pyridinyl derivatives.

The application of this process to the synthesis of 3 - [(3,5-dichloro-4-pyridinyl) methylene] -6-methoxy-1- (3H) -isobenzofuranone is particularly preferred.

In a preferred embodiment of the process object of the present invention, the mixture of compound II, compound III and anhydride is heated under reflux until the reaction is completed. The mixture is evaporated and the residue, taken up with the appropriate solvent and re-evaporated to dryness, can be directly used in the next step.

The process object of the present invention is advantageous above all for the simplicity of implementation and is therefore particularly suitable for industrial application.

It allows to prepare the compounds of formula I, with high yields and in short times, without using the aforementioned salt of phosphonium XI, thus avoiding the related problems, such as for example the formation of unstable brominated intermediates through exothermic reactions, the considerable increase molecular weight and the formation of phosphine oxides.

A further reason of interest is the obtainment of a crude that can be used directly in the subsequent reaction without requiring further purifications. Furthermore, compared to the aforementioned synthetic process reported in international application WO 00/05218, this process allows to reduce the overall number of steps starting from the same derivative of the precursor benzoic acid.

In order to better illustrate the present invention, the following examples are now provided.

Example 1

Preparation of 3 - [(3,5-dichloro-4-pyridinyl) methylene] -6-methoxy-1- (3H) -isobenzofuranone

The mixture prepared at room temperature of 5-methoxy-3-oxo-1,3-dihydro-1-isobenzofuranecarboxylic acid (12.4 g; 0.06 mol), prepared as described in J. Chem. Soc. (1929), 200, and 3,5-dichloro-4-pyridincarbaldehyde (10.8 g; 0.061 mol), prepared according to Heterocycles. (1995), 41, 675, in acetic anhydride (60 ml) was heated under reflux, under stirring, for 30 minutes.

The reaction was evaporated in vacuo, taken up with toluene (50 ml) and evaporated again. This treatment was repeated two more times, obtaining the subject compound (19.3 g; quantitative yield) as a yellow solid.

1H-NMR (200 MHz, CDCl3) δ (ppm): 8.60 and 8.50 (s, 2H, Py); 7.77-6.20 (m, 4H, Ar and CH); 3.90 and 3.80 (s, 3H, OMe); isomer ratio 9: 1.

Example 2

Preparation of 4- [(3,5-dichloro-4-pyridinyl) methyl] - 1.2-dihydro-7-methoxy- 1-phthalazinone

3 - [(3,5-dichloro-4-pyridinyl) methylene] -6-methoxy-1- (3H) -isobenzofuranone (335 g; 1.04 moles) were charged into a 4 liter reactor at room temperature, prepared as described in example 1, and methanol (1785 ml). Then acetic acid (178 ml) were added under stirring and, keeping the temperature below 40 ° C by external cooling, hydrazine monohydrate (171.7 ml) by dripping.

The reaction mixture became a solution, then a new precipitate began to form. The mixture was refluxed for 2 hours. The end of the reaction was checked by TLC (a sample was taken and diluted with CH2Cl2, eluent hexane: ethyl acetate = 7: 3). At the end of the reaction, the mixture was cooled to 0 ° C and filtered. The filtrate was washed with methanol (215 ml). The solid was dried under vacuum at 40 ° C obtaining the subject compound (328.5 g; yield 99%) as a pale yellow solid.

Claims (11)

Claims 1) A process for the preparation of pyridinylidene-phthalides of formula m which Py represents a 2, 3 or 4-pyridinyl group optionally substituted by one or more substituents selected from halogen, nitro, cyano, bone and carboxy groups; R and R1, the same or different from each other, represent hydrogen, C1-C6 alkyl or an OR2 group in which R2 represents a linear or branched C1-C6 alkyl, a C4-C7 cycloalkyl or a C1-C6 polyfluoroalkyl; the bond indicates both isomers E and Z; which comprises the reaction of a compound of formula in which R and R1 have the meanings reported above; with an aldehyde of the formula where Py has the above meaning; by heating the mixture of compounds of formula II and III in the presence of an anhydride and possibly in a mixture with a suitable solvent. 2) A process according to claim 1 wherein Py represents a dialosubstituted 4-pyridinyl group. 3) A process according to claim 2 wherein Py represents a 3,5-dichloro-4-pyridinyl group. 4) A process according to claim 1 wherein one or both of R and R1 represent OCH3. 5) A process according to claim 1 in which the compounds of formula III are used with respect to the compounds of formula II in a molar ratio comprised between 0.5 and 4. 6) A process according to claim 5 in which the compounds of formula III are used with respect to the compounds of formula II in a molar ratio of between 0.8 and 1.5. 7) A process according to claim 6 in which the compounds of formula III are used with respect to the compounds of formula II in a molar ratio comprised between 0.9 and 1.1. 8) A process according to claim 1 in which the anhydride is an organic anhydride. 9) A process according to claim 8 in which the anhydride is acetic anhydride. 10) A process according to claim 1 in which the anhydride is used in excess. 11) A process for the preparation of formula phthalazines in which R, R1 and Py have the meanings reported above; it is a single or double bond; Y represents two hydrogen atoms or a group = 0 when it is a single bond, or when it is a double bond Y is hydrogen, cyano, (C1-C4) -alkoxycarbonyl, amido, aryl or possibly substituted heterocycle, (C1-C8-alkyl, (C2-C8) -cyclylamino; W is absent when it is a double bond or, when it is a single bond, it represents a) hydrogen; b) (C1-C6) -alkyl optionally substituted by aryl, heterocycle or by a COR5 group where R5 is hydroxy, (C1-C4) -alkoxy or hydroxyamino; c) -COR6 where R6 is hydrogen, aryl, aryl- (C1-C6) -alkyl, amino optionally alkylated or monohydroxylated, hydroxy, (C1-C4) -alkoxy, carboxy, (C1-C4) -alkoxycarbonyl, or ( C1-C4) -alkyl optionally substituted by heterocycle; d) (C1-C4) -alkylsulfonyl; which includes the preparation of the intermediate of formula I in which R, R1 and Py have the meanings reported above; according to the process of claim 1.